[.sup.3 H]1-[1-(2-thienyl)cyclohexyl]cyclohexyl]piperidine (TCP), an analog of the dissociative anesthetic phencyclidine (PCP), binds with high affinity to two sites in guinea pig brain membranes, one of which is MK-801 sensitive and one of which is not. The MK-801-sensitive site (PCP site 1) is associated with NMDA receptors. The MK-801-insensitive site (PCP site 2) is thought to be associated with biogenic amine transporters (BAT) (Rothman, R. B., et al. Mol. Pharmacol. 36:887-896 (1989); Akunne, H. C., et al. Synapse 8:289-300 (1991); Rothman, R. B., et al., In: Multiple Sigma and PCP Receptor Ligands: Mechanisms for Neuromodulation and Protection, pp. 137-146 (Domino, E. F. and Kamenka, J. M., eds., 1992); Akunne, H. C., et al. Neurochem. Res. 17:261-264 (1992)).
Based upon the association of PCP site 2 with BATs, drugs with high affinity for PCP site 2 would be expected to inhibit the reuptake of biogenic amines.
The present invention is directed to classes of compounds which bind selectively and potently to PCP site 2 and also have activity as biogenic amine transport blockers. (2RS, 3aSR, 8aRS)-1,2,3a,8,8a-Hexahydro-2-benzyl-1-methyl-indeno[1,2-b]pyrrole (RTI-4793-14) represents the first of these compounds which bind with high affinity to biogenic amine transporters but are relatively less potent amine reuptake blockers than classical BAT ligands. This compound has been shown to increase the levels of dopamine in the brain and thus would be useful for treating diseases or disorders characterized by dopamine deficiency such as Parkinson's Disease and depression. The compound also would be useful in radioligand binding studies to label the PCP site 2 because of its high affinity and selectively for PCP site 2.
Hungarian Patent No. 151,567 disclosed ideno [1,2-b]pyrroles having the structure below wherein R1 is hydrogen, aryl, or a heteroaryl group and R2 is a H or an alkyl group (see also Chemical Abstracts, vol. 62, No. 528(g) (1965)). Some of these compounds have antispasmatic or tranquilizing properties. ##STR3##
De and Saha disclosed ideno [1,2-b]pyrroles having the structure below wherein R is an alkyl group such as methyl, ethyl, propyl, butyl, or pentyl (De, A. U. and Saha, B. P., J. Pharm. Sci. 62(8): 1363-1364 (1973); De, A. U. and Saha, B. P., J. Pharm. Sci. 64(2): 249-252 (1975)). These compounds were screened as possible oral hypoglycemic agents. ##STR4##